This invention relates to the treatment of fungal infections with estrogenic derivatives.
Candidiasis is a fungal infection of mucosal membranes and other tissues. The infection is caused by the yeast-like organism Candida. Numerous species of Candida exist, including C. albicans. The recent increase in candidiasis is most likely caused by the rising incidence of AIDS, more intensive regimens of cancer therapy, complications of abdominal or cardio-thoracic surgery, organ transplantations, burns and trauma. Immunocompromised individuals and women of childbearing age, especially pregnant women or women with one or more child births, are known to be more susceptible to microbial pathogenesis. Alteration of the fungi microenvironment is currently considered to be accountable for the initiation of C. albicans infection symptoms (1). Changes in pH, temperature, osmotic pressure, and hormonal concentrations are some of the environmental factors that induce virulence expression.
While most candidiasis patients are infected with C. albicans, the number of non-C. albicans infections has been growing steadily and may reflect the increased use of azole drug prophylaxis and therapy since some non-C. albicans species are innately resistant to these drugs. Additional risk factors commonly associated with the onset of candidiasis include protracted, broad-spectrum antibiotic therapies, invasive devices, and prolonged hospital stays. Under these conditions, an antibiotic resistant replacement flora, including one or more fungal species, can proliferate in the gastrointestinal tract and invade from mucosal foci to deep tissues, especially when mucosal integrity has been disrupted as a result of chemotherapy or surgery.
2-Methoxyestradiol (2ME2), an end product of 17xcex2-estradiol metabolism, is a well-known anti-mitogen that suppresses the growth of rapidly dividing mammalian cells by interfering with the progression of their cell cycle. Although a number of studies have been published regarding the effects of 2ME2 and related derivatives on the proliferation of endothelial and tumor cells, nothing is known about the effects of this metabolite on the replication of non-mammalian cells.
Recently, 17xcex2-estradiol has emerged as one of the agents that support C. albicans germination and growth (1, 2). Specifically, growth of yeast cells in serum stripped of any steroid compound (by means of activated charcoal) results in reduction of the percentage of germinating cells, and thus, in reduction in virulence. Supplementation of the stripped media with exogenous estradiol in nanomolar concentrations restores germination. This property is specific to 17xcex2-estradiol, since cholesterol and the xcex1-isomer of estradiol do not induce morphogenic changes in C. albicans. In addition, certain strains of C. albicans require the presence of 17xcex1- or 17xcex2-estradiol for rapid growth.
The importance of estrogen as a virulence factor is also reinforced by in vivo studies in which estrogen treatment is required to induce susceptibility of oophorectomized to vaginal colonization of C. albicans (3, 4), and the presence of an estrogen-binding protein (EBP) in C. albicans that binds to estrogen with high affinity and specificity (5, 6).
The present invention provides compounds that are useful for inhibiting the growth of fungi. The compounds are estrogenic derivatives, such as 2ME2, and analogs thereof. The compounds may be used for treating infections of fungi in humans and animals, or to prevent or inhibit the growth of fungi on any surface. Furthermore, the invention contemplates the use of anti-estrogenic compounds, such as tamoxifen and raloxifene, as anti-fungal treatments.